Understanding and Enhancing T-Cell Responses to High Risk Human Papillomaviruses

了解和增强 T 细胞对高风险人乳头瘤病毒的反应

• 批准号: 9036591
• 负责人: Mayumi Nakagawa
• 金额: $ 54.5万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036591
• 关键词: Adjuvant; Adverse effects; Age; Anatomy; Anus; Biopsy; Cancer Burden; Cancer Etiology; Candida; Cellular Immunity; Cervical; Cervical Intraepithelial Neoplasia; Child; Clinical; Clinical Trials; Common wart; Contraceptive Usage; Diagnosis; Dose; Double-Blind Method; Epitopes; Excision; FDA approved; Future; Goals; Guidelines; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papillomavirus 16; Hypersensitivity skin testing; Immune; Immune response; Incidence; Individual; Injection of therapeutic agent; Lead; Length; Lesion; Malignant Neoplasms; Malignant Vaginal Neoplasm; Malignant neoplasm of cervix uteri; Malignant neoplasm of penis; Malignant neoplasm of vulva; Measurable; Modality; Odds Ratio; Operative Surgical Procedures; Oral Contraceptives; Outcome; Patients; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Placebo Control; Placebos; Population; Premature Birth; Prevention; Procedures; Proteins; Publishing; Randomized; Reagent; Recommendation; Regulatory T-Lymphocyte; Respondent; Risk; Safety; Smoking History; Squamous intraepithelial lesion; T cell response; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Time; Vaccination; Vaccine Adjuvant; Vaccines; Vulva; Woman; Work; arm; base; chemokine; cross reactivity; cytokine; high risk; human leukocyte antigen testing; individualized medicine; intraepithelial; malignant oropharynx neoplasm; mortality; novel vaccines; phase 2 study; prevent; prophylactic; public health relevance; response; synthetic peptide; therapeutic vaccine; vaccine development; vaccine response; young woman

 DESCRIPTION (provided by applicant): The long-term goal of this project is to develop a therapeutic human papillomavirus (HPV) vaccine that would prevent cervical cancer and other cancers caused by high-risk HPV types in individuals already infected, at which point currently available HPV prophylactic vaccines are not effective. This competitive renewal application proposes to conduct a Phase II clinical trial treating women with biopsy-proven high-grade squamous intraepithelial lesions (HSILs). HSILs are precursors of cervical cancer, which is almost always caused by HPV and is the fourth most common cancer among women worldwide, with annual incidence of 528,000 cases and mortality of 266,000 cases. In addition, HPV causes anal, oropharyngeal, penile, vaginal, and vulvar cancers; it is estimated that HPV is responsible for 5.2% of the cancer burden. Standard surgical treatments for HSILs are effective but have the unintended consequence of doubling the rate of preterm delivery afterward. Therefore, an alternative, such as a therapeutic HPV vaccine, is needed that would work by stimulating cell-mediated immunity without compromising cervical anatomy. Our group is developing an HPV therapeutic vaccine - PepCan - that consists of four "current good manufacturing grade" synthetic peptides that cover the E6 protein of HPV type 16 (HPV 16), along with a Candida skin-test reagent as a novel vaccine adjuvant. The immune response to the E6 protein has been associated with good clinical outcomes in naturally HPV-infected women with and without cervical lesions, and Candida injection has been shown to regress common warts and induce T-cell responses. The ongoing Phase I clinical trial has demonstrated safety, immunological responses, and histological regression above that of a historical placebo control. The proposed Phase II study will assess efficacy by extending the observation period from 3 months (in Phase I) to 1 year, which is the length of time required for similar therapeutic vaccines to take full effect. As efficacy was demonstrated against HSILs associated and not associated with HPV 16, a Candida treatment arm will be added in a randomized, double-blinded fashion. The additional goals are to identify factors associated with vaccine response, examine vaccine effect, and define the other HPVs that can be treated with PepCan. We hypothesize that PepCan induces HSIL regression and HPV clearance by mounting immune responses with measurable signatures against multiple HPV types. This hypothesis will be tested with the following aims: Aim 1: assess efficacy and safety of our HPV therapeutic vaccine in a Phase II clinical trial; Aim 2: identify factors associated with a favorable vaccine response, and examine the effects of vaccination; and Aim 3: describe non-HPV 16 types against which this vaccine is effective. Epitope spreading, cross-reactivity of T cells, and de novo immune stimulation will be investigated as possible mechanisms of cross-protection. Successful completion of this project should lead not only to an FDA-approved HPV therapeutic vaccine for cervical cancer but also to a new modality for prevention and treatment of all cancers caused by HPV.

 描述(申请人提供)：该项目的长期目标是开发一种治疗性人乳头瘤病毒(HPV)疫苗，以预防已感染高危HPV类型的人患宫颈癌和其他癌症，目前可用的HPV预防性疫苗在这一点上无效。这项竞争性更新申请建议进行第二阶段临床试验，治疗经活检证实的高度鳞状上皮内病变(HSILs)的妇女。HSIL是宫颈癌的先兆，宫颈癌几乎总是由HPV引起，是全球第四大最常见的癌症，每年的发病率为52.8万例，死亡率为26.6万例。此外，HPV还会导致肛门癌、口咽癌、阴道癌、阴道癌和外阴癌；据估计，HPV对癌症负担的5.2%负有责任。标准的手术治疗对HSIL是有效的，但有意想不到的后果，即后来早产率翻了一番。因此，需要一种替代方案，例如治疗性HPV疫苗，这种疫苗可以在不损害宫颈解剖的情况下，通过刺激细胞介导的免疫发挥作用。我们小组正在开发一种HPV治疗性疫苗-PepCan-它由四个覆盖HPV16型(HPV16)E6蛋白的“目前良好的制造级”合成肽组成，以及一种作为新型疫苗佐剂的念珠菌皮试试剂。在有或没有宫颈病变的自然感染HPV的妇女中，对E6蛋白的免疫反应与良好的临床结果有关，念珠菌注射已被证明可以消退常见的尖锐湿疣并诱导T细胞反应。正在进行的I期临床试验证明，与历史上的安慰剂对照相比，安全性、免疫学反应和组织学退化都要好于历史上的安慰剂对照。拟议的第二阶段研究将评估疗效，将观察期从三个月(第一阶段)延长至一年，这是类似治疗性疫苗完全生效所需的时间长度。由于对与HPV16相关和不与HPV16相关的HSIL有疗效，将以随机、双盲的方式增加一支念珠菌治疗臂。其他目标是确定与疫苗反应相关的因素，检查疫苗效果，并确定可以用PepCan治疗的其他HPV。我们假设PepCan通过建立针对多种HPV类型的可测量签名的免疫反应来诱导HSIL回归和HPV清除。这一假设将通过以下目标进行检验：目标1：在第二阶段临床试验中评估我们的HPV治疗性疫苗的有效性和安全性；目标2：确定与有利的疫苗反应相关的因素， 并检查接种疫苗的效果；以及目标3：描述该疫苗对哪些非HPV16型有效。交叉保护的可能机制包括表位扩散、T细胞的交叉反应和从头免疫刺激。该项目的成功完成将不仅导致FDA批准的宫颈癌HPV治疗性疫苗，而且还将导致一种预防和治疗由HPV引起的所有癌症的新方法。